The invention relates to compositions and methods for the treatment and prevention of anxiety, convulsive disorders, and other disorders.
Zopiclone, chemically named (xc2x1)-6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4b]pyrazin-5-yl-4-methylpiperazine-1-carboxylate, is a non-benzodiazepine hypnotic which has the following structure: 
Zopiclone and some of its uses are described by U.S. Pat. Nos. 3,862,149 and 4,220,646. Uses of the optically pure (+) and (xe2x88x92) enantiomers of the drug (i.e., (+)-zopiclone and (xe2x88x92)-zopiclone) are described by U.S. Pat. No. 5,786,357 and WO 93/10788, respectively.
Zopiclone binds at or near benzodiazepine receptor complexes. Goa, K. L. and Heel, R. C. Drugs, 32:48-65 (1986). These complexes are located both within the central nervous system and peripherally (e.g., in the endocrine system), and contain macromolecular complexes which comprise benzodiazepine and GABA binding sites. Verma, A. and Snyder, S. H., Annu. Rev. Pharmacol. Toxicol. 29:307-22 (1989). Benzodiazepine receptor complexes are further associated with, and interact with, membrane channels for chloride ion transport. Upon binding to a benzodiazepine receptor complex, zopiclone is believed to allosterically modulate the activity of the complex by increasing trans-membrane conductance of chloride ions. This stabilizes neuronal membrane potentials and dampens excitatory input. See Meldrum, B. S., Brit. J. Clin. Pharm. 27(suppl. 1):3S-11S (1989); Goodman and Gilman""s The Pharmacological Basis of Therapeutics, Hardman, J. G., et al., eds. p. 365 (9th ed., 1996).
Although chemically unrelated to the benzodiazepines, zopiclone possesses a spectrum of activity analogous to that of the benzodiazepines. Goa, K.L. and Heel, R. C. Drugs, 32:48-65, (1986). Zopiclone and its optically pure enantiomers are reportedly useful in the treatment of diseases and conditions including, but not limited to, epilepsy, anxiety, aggressive behavior, muscle tension, behavioral disorders, depression, schizophrenia, and endocrine disorders. See, e.g., WO 93/10787. Racemic zopiclone has been used to improve sleep in adults and geriatric patients with several types of sleep disorders including situational, transient primary and secondary insomnia. See, e.g., Brun, J. P., Pharm. Biochem. Behav. 29:831-832 (1988).
Some compounds which bind at benzodiazepine receptors can also have affinity for muscarinic receptors such as acetylcholine receptors. Julou, L., et al., Pharmacol. Biochem. Behav. 23:653-659 (1985). Consequently, administration of such compounds can result in adverse effects caused by muscarinic agonists and antagonists. Such adverse effects include, but are not limited to, drymouth, thirst, slowing and acceleration of the heart, dilated pupils, blurred vision, restlessness, fatigue, headache, hallucinations and delirium. Goodman and Gilman""s The Pharmacological Basis of Therapeutics, Hardman, J. G., et al., eds. p. 142 (9th ed., 1996).
The metabolism of zopiclone is rapid and complex. When administered orally to healthy humans, the racemic drug is extensively metabolized by at least three major pathways, as shown below in Scheme 1. 
Metabolic pathways include oxidation, hydrolysis, and demethylation. An oxidation pathway produces N-oxidezopiclone, a metabolite which is reportedly less active than zopiclone and reportedly accounts for 11% of an oral dose of racemic zopiclone. A hydrolysis pathway produces an alcohol which is reportedly biologically inactive. A demethylation metabolic pathway produces N-desmethylzopiclone, a metabolite which reportedly accounts for 15% of an oral dose of racemic zopiclone, and which is also reportedly inactive. Goa, K. L. and Heel, R. C. Drugs, 32:48-65, (1986). Additional metabolites are formed from each of the three pathways shown in Scheme 1.
The full pharmacological activity of zopiclone is reportedly due to the drug itself and the N-oxide metabolite (i.e., N-oxidezopiclone). Id. Unfortunately, the single-dose elimination half-lives of both of these compounds after administration of racemic zopiclone range from only about 3.5 to about 6 hours, which limits the usefulness of zopiclone in the treatment of a wide number of disorders. For example, the rapid elimination of zopiclone and N-oxidezopiclone limits their usefulness in long-term anxiolytic treatment. The single-dose elimination half-life of the reportedly inactive N-desmethyl-zopiclone metabolite (herein referred to as xe2x80x9cN-desmethylzopiclonexe2x80x9d) after administration of racemic zopiclone is between about 7 and about 11 hours in healthy subjects. Id.
Racemic zopiclone possesses further disadvantages, in particular, it causes adverse side effects which include, but are not limited to, the development of a bitter taste due to salivary secretion of the drug, dry mouth, heart palpitations, drowsiness, morning tiredness, headache, dizziness, impairment of psychomotor skills and related effects. A compound is thus desired for the treatment or prevention of various disorders which does not possesses disadvantages associated with racemic zopiclone.
The invention is directed to compositions comprising, and methods of using, racemic N-desmethylzopiclone ((xc2x1)-N-desmethylzopiclone), optically pure (+)-N-desmethylzopiclone, and optically pure (xe2x88x92)-N-desmethylzopiclone in the treatment and prevention of diseases and conditions in mammals.
One embodiment of the invention encompasses a method of treating or preventing anxiety in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. One method of this embodiment is the treatment or prevention of acute anxiety. Another method of this embodiment is the treatment or prevention of chronic anxiety. Yet another method of this embodiment is the treatment or prevention of general anxiety disorder. In a preferred method of this embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer.
Another embodiment of the invention encompasses a method of treating or preventing a convulsive state in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. A particular method of this embodiment is the treatment or prevention of epilepsy or epileptic seizures. In a preferred method of this embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer.
Yet another embodiment of the invention encompasses a method of treating or preventing an affective disorder in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. A particular method of this embodiment is the treatment or prevention of depression. Another method of this embodiment is the treatment or prevention of attention deficit disorder or attention deficit disorder with hyperactivity. In a preferred method of this embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer.
A further embodiment of the invention encompasses a method of treating or preventing a sleep disorder in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. A particular method of this embodiment is the treatment or prevention of insomnia. In a preferred method of this embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer.
Another embodiment of the invention encompasses a method of treating or preventing aggressive behavior in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. In a preferred method of this embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer.
Still another embodiment of the invention encompasses a method of treating or preventing spasticity or acute muscle spasm spasticity in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. In a preferred method of this embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer.
Yet another embodiment of the invention encompasses a method of treating or preventing a behavioral disorder in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. In a preferred method of this embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer.
Still another embodiment of the invention encompasses a method of treating a schizophrenic disorder in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. In a preferred method of this embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer.
Still another embodiment of the invention encompasses a method of treating or preventing a disease or condition associated with abnormal plasma hormone levels in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. In a particular method of this embodiment, the disorder is an endocrine disorder. In a preferred method of this embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer.
Still another embodiment of the invention encompasses a method of treating alcohol or drug addiction in a patient which comprises administering to a patient in need of such treatment a therapeutically effective amount of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. In a preferred method of this embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer.
Still another embodiment of the invention encompasses a method of treating or preventing drug withdrawal, alcohol withdrawal, symptoms of drug withdrawal, or symptoms of alcohol withdrawal in a patient which comprises administering to a patient in need of such treatment a therapeutically effective amount of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. Examples of such symptoms are disclosed herein. In a preferred method of this embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer.
Patients who may receive the therapeutic or prophylactic benefits of the methods of the invention include those suffering from the diseases or conditions described above, as well as patients suffering from cancer, patients currently being treated with a muscarinic antagonist or a muscarinic agonist, and patients who are susceptible to adverse effects associated with racemic zopiclone.
A further embodiment of the invention encompasses pharmaceutical compositions comprising N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. In preferred pharmaceutical compositions, N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free of its (xe2x88x92) enantiomer. Typical pharmaceutical compositions of the invention will comprise N-desmethylzopiclone and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical compositions of the present invention are free of lactose (lactose-free), or other mono- or disaccharides. In another alternative embodiment, pharmaceutical compositions of the invention are anhydrous or anhydrous and lactose-free.
Also encompassed by the invention are single unit dosage forms of racemic and optically pure enantiomers of N-desmethylzopiclone, or pharmaceutically acceptable salts, solvates, hydrate, or clathrates thereof. Single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration. Preferred single unit dosage forms of racemic and optically pure (+)- or (xe2x88x92)-N-desmethylzopiclone are suitable for oral administration. Most preferred single unit dosage forms of racemic and optically pure (+)- or (xe2x88x92)-N-desmethylzopiclone are tablets, capsules and caplets.
Another embodiment of the invention encompasses methods of preparing optically pure enantiomers of N-desmethylzopiclone. One method comprises treating an optically pure enantiomer of zopiclone with 1-chloroethyl chloroformate. Another method comprises treating an optically pure enantiomer of zopiclone with an azodicarboxylate, and hydrolyzing the resulting product under mild conditions. A preferred azodicarboxylate is diethyl azodicarboxylate. Yet another method of this embodiment comprises resolution of racemic desmethylzopiclone using L-N-benzyloxycarbonyl phenylalanine (L-ZPA) as a resolution reagent.